Imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity

Abstract

Imino sugars, such as deoxynojirimycin (DNJ), are glucose analogues that selectively inhibit cellular α-glucosidase I and II (enzymes that process N-linked glycans in glycoprotein) and exhibit broad spectrum antiviral activities against many enveloped viruses. Previously we have reported a novel DNJ derivative, OSL-95II, with antiviral activity and reduced cytotoxicity. In order to develop imino sugars with more potent antiviral activity as well as improved toxicity profile, OSL-95II was modified by diversifying the nitrogen linked alkylated side chain. The antiviral activities were initially tested in bovine viral diarrhea virus (BVDV) infected MDBK cells, yielding several imino sugar derivatives with novel structure and superior antiviral activity and toxicity profile. Furthermore, these new compounds were shown to be active against Dengue virus (DV) and West Nile virus (WNV) infection in BHK cells where potent anti-DV activity having submicromolar EC50 values and SI of greater than 900. These compounds represent a new generation of iminio sugars and their analogues, having application in the clinical treatment of infection of DV and other members of flaviviridae.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a non-provisional application, the entire contents of which is incorporated by reference herein and claims priority, in part, of U.S. Provisional Application No. 61 / 190,618, filed 2 Sep. 2008 and International Application PCT / US2009 / 055658, filed 2 Sep. 2009.BACKGROUND[0002]1. Field[0003]This invention relates to the field of antiviral compounds and compositions for the treatment against flaviviral infections. More specifically, it relates to N-pentyl-(1-hydroxycyclohexyl)-DNJ derivatives and their use as pharmaceutical compositions in the treatment and prevention of Dengue, West Nile, Japanese Encephalitis virus, Bovine viral diarrhea virus, and hepatitis C.[0004]2. Background Art[0005]Imino sugars are broad-spectrum antiviral agents that interfere with virus assembly through glucosidase inhibition. Dengue virus has an envelope protein with a specific structure that makes it more sensitive to imino sugar treatment. Co...

AI Technical Summary

Benefits of technology

[0017]29 structurally-related compounds having alkylated DNJs with cyclized side chains of OSL-95II were synthesized and evaluated, among which, a group of compounds, as represented by CM-9-78, with oxygenated alkyl chain and terminal ring structure stood out to have better efficacy and lower cytotoxicity. Further modification of terminal ring structure on CM-9-78 resulted in the PBDNJ series of compounds, which have a high potency for inhibition of DV infection in vitro with EC90 values at submicromolar concentrations. This group of PBDNJ compounds are representative of a class of compounds whereby realistic candidates for the development of antiviral therapy against human dengue virus infections and other clinically relevant disorders are possible.

Problems solved by technology

Thus, inhibition of α-glucosidases leads to the misfolding and degradation of glycoproteins where this specific interaction is required.

The development of a imino sugar glucosidase inhibitor is limited by low efficacy and / or cytotoxicity.

More specifically, Dengue virus (DV) infection is a growing world health problem and a bio-terror concern.

Thus far, effective antiviral therapies and vaccines are not yet available to treat or prevent DV infection.

Moreover, the emergence of resistant virus would be expected to be rare.

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